Hypercompressed (densified) biologically compatible lactide polymer, glycolactide or lactide-glycolactide copolymers containing APIs are known. For many applications of these products, it is desirable to utilize radiation to sterilize these products prior to administration to or implantation in a patient. However, these hypercompressed polymers or copolymers are susceptible to degradation when sterilized with radiation. When the API is a thermally unstable material such as a polypeptide or a protein, it is essential to use radiation for sterilization because those solid formulations may only be sterilized by radiation as production of these products in a sterile by process method is not practicable. The applicant has observed that when gamma radiation is applied to make a sterile product based on a polymeric material comprising a lactide polymer, glycolactide or lactide-glycolactide copolymer, these polymeric materials and any polypeptide or protein, which is present, may be degraded or denatured. This can result in a product where the API fails to meet regulatory standards for potency.
It is known that ionizing radiation interacts with the electrons of polymer molecules with a transfer of energy that results in ion formation and ejection of secondary electrons. Depending on the level of kinetic energy of the secondary electrons, there can be further ionization and excitation of other molecules present in the vicinity. The immediate outcome of the exposure to ionizing radiation, such as gamma radiation, is the formation of various energetic species such as trapped radicals, electrons and ions; the decays of these energetic species results in fragmentation and generates free radicals. Such events can both destabilize (chain scission) and stabilize (crosslinking) the polymeric material and or the API.
A significant factor affecting the interaction between the reactive species of degraded peptides and proteins is their proximity to each other. Since hypercompression positions reactive species in closer proximity to one another, the hypercompression actually can facilitate further degradation which results in a reduction in the potency of the product as well as a less stable product with a shorter shelf life.
Current pharmaceutical regulations exist in the United States and in Europe that limit the amount of substances in pharmaceuticals which are related to the active pharmaceutical ingredient to no more than 1.0 wt % or 5 μg TDI (total daily intake) whichever is lower. for a maximum daily dose of 1.0 mg. These related substances have been detected in radiation sterilized polymer or copolymer containing pharmaceuticals at levels that make the products unusable for therapeutic purposes.
It has been found that when a hypercompressed dexamethasone/PLGA product is sterilized by gamma-irradiation, the results show that the level of radiation induced degradation byproducts are relatively high (2.35% when acid terminated PLGA was used and 2.16% when ester-capped PLGA was used). When electron beam irradiation for sterilization is used with ester capped PLGA, the radiation induced degradation byproduct was substantially reduced (between 0.89% to 1.03%).
The present invention is based on the discovery that the use of an electron beam sterilization technique avoids the degradation problems that arise with gamma radiation sterilization of hypercompressed pharmaceutical controlled release products made with ester capped lactide polymers, ester capped glycolactide polymers or ester capped lactide-glycolactide copolymers.